Adagrasib alone, with cetuximab shows ‘encouraging’ activity in advanced colorectal cancer
Click Here to Manage Email Alerts
Adagrasib alone and in combination with cetuximab exhibited promising efficacy compared with historical outcomes among heavily pretreated patients with advanced colorectal cancer who had KRASG12C mutations.
The agent — both alone and as part of combination therapy — also exhibited a favorable safety profile, according to researchers who presented results of the phase 1/phase 2 KRYSTAL-1 study at ESMO Congress.
An estimated 3% to 4% of people with colorectal cancer harbor KRASG12C mutations, and patients with these alterations typically do not survive as long after standard chemotherapy as those without such mutations. Preclinical data suggested dual blockade of EGFR and KRASG12C may enhance inhibition of KRAS-dependent signaling, according to study background.
Adagrasib (MRTX849, Mirati Therapeutics) is an investigational KRASG12C inhibitor that irreversibly locks the mutant protein in its inactive state.
The multicohort KRYSTAL-1 study assessed adagrasib with or without cetuximab (Erbitux, Eli Lilly) — a monoclonal antibody that inhibits EGFR — for patients with advanced colorectal cancer who harbored KRASG12C mutations.
The analysis included 76 patients.
Forty-four (median age, 59 years; 50% women) received adagrasib dosed at 600 mg twice daily. A comparable percentage had ECOG performance status of 0 (52%) or 1 (48%).
The other 32 patients (median age, 60 years; 53% women) received adagrasib at the same dose, plus cetuximab dosed at 400 mg/m2 followed by 250 mg/m2 weekly or 500 mg/m2 every 2 weeks. All patients in the combination group had ECOG performance status of 0 (44%) or 1 (56%).
All study participants had received a median three lines of prior systemic therapy.
Median follow-up was 20.1 months in the adagrasib monotherapy group and 17.5 months in the adagrasib-cetuximab group.
Among 43 evaluable patients who received adagrasib monotherapy, researchers reported a 19% confirmed objective response rate and an 86% disease control rate, with a median response duration of 4.3 months (95% CI, 2.3-8.3) and median PFS of 5.6 months (95% CI, 4.1-8.3).
Among 28 evaluable patients in the combination group, researchers reported a 46% confirmed ORR and a 100% disease control rate, with a median response duration of 7.6 months (95% CI, 5.7-not estimable) and median PFS of 6.9 months (95% CI, 5.4-8.1).
In the monotherapy group, more than half (59%) of study participants experienced grade 1/grade 2 treatment-related adverse events, and 34% experienced grade 3/grade 4 treatment-related events. In the combination group, 84% experienced grade 1/grade 2 treatment-related adverse events and 16% experienced grade 3/grade 4 events. Investigators observed no grade 5 treatment-emergent adverse events.
“These data illustrate the importance of durable KRAS inhibition in colorectal cancer and the added benefit that dual EGFR/KRAS blockade may provide for some patients in their regimen as evidenced by the more sustained responses from the adagrasib and cetuximab combination,” researcher Samuel J. Klempner, MD, medical oncologist at Mass General Cancer Center, said in a Mirati Therapeutics-issued press release. “Overall, it's encouraging to see the emergence of KRAS inhibitors like adagrasib providing more targeted, efficacious and safe treatment options for colorectal cancer and other solid tumors with KRAS mutations."
References:
- Klempner SJ, et al. Abstract LBA24. Presented at: European Society for Medical Oncology Congress; Sept. 9-13, 2022; Paris.
- Mirati Therapeutics presents late-breaking adagrasib monotherapy and combination results in advanced colorectal cancer (press release). Available at: www.yahoo.com/now/mirati-therapeutics-presents-breaking-adagrasib-220500005.html. Published Sept. 7, 2022. Accessed Sept. 12, 2022.
Collapse
Klempner SJ, et al. Abstract LBA24. Presented at: European Society for Medical Oncology Congress; Sept. 9-13, 2022; Paris.
Click Here to Manage Email Alerts